**3.2 Pregnancy immunology: when the miracle has already taken place!**

Progesterone is essential for the initiation and maintenance of pregnancy as it has important effects on the immune system [13]. These effects are coordinated by a progesterone-induced blocking factor (PIBF). This is encoded in a target gene located on chromosome 13 in humans. This protein has some isoforms, which act as cytokines, that exert their action on the metabolism of arachidonic acid, inhibit arachidonic acid by the direct action of phospholipase A2 and the subsequent decrease in prostaglandin and/or leukotriene synthesis.

#### *Fertility, Pregnancy, and Systemic Lupus Erythematosus DOI: http://dx.doi.org/10.5772/intechopen.107036*

Full-length PIBF (90 kDa) is anchored in the nucleus and is involved in cell-cycle regulation. The expression of PIBF seems to be crucial for the normal progression of pregnancy, which is why it is found in the lymphocytes of pregnant women as well as in other tissues inherent to pregnancy and has also been found to be related to the proliferation of cancer cells in tumors malignant [14]. The decreased production of this factor results in an alteration of the cell cycle with the consequent deregulated and uncontrolled invasion of the trophoblast, if it is the isoforms that are absent, it could result in the loss of local immunosuppression, necessary for maintenance and vitality of gestation.

NK (natural killer) cells tend to differentiate during pregnancy. While ordinarily, 90% of peripheral NK cells express a low density of CD56dim molecules and high levels of CD16; most decidual NK cells express a high density of CD56bright and not CD16. These secrete angiogenic factors and cytokines, and one of their functions is to control placentation in an orderly and adequate manner [15]. Peripheral CD56dim NK cells are cytotoxic, whereas CD56bright are not. The job of PIBF is to inhibit the release of perforins from activated peripheral NK cells and this, in turn, helps to maintain the low level of lytic activity of decidual NK cells.

It is understood that during pregnancy there is a predominantly Th2 immune response; however, there are certain moments of it where there is a change in response, for example at the time of implantation or at the time of childbirth.

Evidently, progesterone and PIBF alter cytokine homeostasis in favor of a Th2 response. And so, a nonhostile immune environment is promoted by the increase in IL-10 and regulatory T cells [16]. This response slowly changes and gradually reverses before the onset of labor. Progesterone reduces proinflammatory and cytotoxic T-cell responses by effectively modulating immune cell-mediated interactions and regulating differentiated memory cells. In a normal gestation process, PIBF in urine and serum increases until the 37th week of gestation, followed by a sharp decrease in labor. Whereas, in a pathological pregnancy, the levels of PIBF in urine do not increase. The onset of labor (both term and preterm) is predictable based on PIBF levels [17].

## **3.3 Immunology of pregnancy: the dance of the mother/fetus binomial**


We forget the very important role of the major histocompatibility complex (MHC) that protects the trophoblast from the destruction of the NK by inhibiting its lytic functions, as well as limits the cytotoxic activity of leukocytes, suppresses the

#### **Figure 2.**

*Sequence of events in the immunology of pregnancy between the mother/fetus binomial.*

production of cytokines of type proinflammatory, and also induces T cell apoptosis. [19]. Nonclassical MHC antigens also promote trophoblast proliferation and invasion. Altered expression of nonclassical MHC 501 antigens has been linked to recurrent pregnancy loss and preeclampsia. Placental expression of FAS ligand may also play a role in pregnancy success through the selective removal of antifetal T-cell clones.

#### **3.4 Fetal Immune System**

It begins at the moment of conception and continues until birth and later in infancy. In the first weeks of gestation, pluripotent stem cells form all the components of blood cells. In the sixth week, the thymus forms and lymphocyte differentiation begin. Subsequently, the first lymphocyte bud appears along with the plexuses. At the end of the first trimester of pregnancy, the fetus already has the ability to respond, although it decreases infections because there is already production of plasma cells and antibodies.

The trophoblast continues to develop as a barrier that is not entirely infallible but is effective in preventing the passage of cells with immunological capacity. Even thought maternal IgG action of placental Fc receptors passes a barrier levels are barely perceptible at the beginning of pregnancy; they have a slow increase in the second trimester and equal and reach maternal serum concentrations at 26 weeks of gestation reaching its maximum transfer in the last 4 weeks of gestation. Humoral immunity in the neonatal period depends exclusively on circulating immunoglobulins that have crossed the placenta. This is why potentially harmful maternal autoantibodies (anti-SSA, anti-SSB, and anticardiolipin) will pass into the fetal circulation and will have harmful potential just as maternal exposure to IgG-based pharmaceutical agents will also pass into the fetal circulation [20].

#### **4. Pregnancy and lupus: when we have to face troubled waters!**

Pregnancy in women with SLE, especially those with significant renal involvement (lupus nephritis), is associated with an increased risk of developing preeclampsia,

*Fertility, Pregnancy, and Systemic Lupus Erythematosus DOI: http://dx.doi.org/10.5772/intechopen.107036*

#### **Figure 3.**

*Consequences of pregnancy in patients with chronic kidney disease and SLE.*

fetal growth restriction, fetal loss, and preterm delivery. This risk remains latent, although lupus nephritis is inactive and rises considerably in cases where it is accompanied by proteinuria and/or high blood pressure. If there is already severe kidney damage, the possibility of pregnancy without problems is remote (**Figure 3**) [10].

Lupus activity is a key predictor of pregnancy outcome. High levels of lupus activity before the start of pregnancy increased the risk of pregnancy loss and the risk of preterm delivery up to four times, the latter together with elevated anti-DNAdc (anti-double-stranded DNA antibodies) and low complement [21]. There are other biomarkers that can give clues about poor pregnancy outcomes in patients with SLE: Elevated ferritin as a marker of inflammation and low estradiol as a marker of poor placentation, are associated with preterm birth. In a meta-analysis where 362 patients with SLE were studied, their pregnancies showed an incidence of renal flare from 11% to 43%, acute kidney injury from 3% to 27%, and total loss of renal function in 11%. In another study, 113 pregnancies were evaluated in 81 women with preexisting biopsy with lupus nephritis (six women with class II, eight with class III, 48 with class IV, and 19 with class V). At the beginning of the pregnancy, 49% were in complete remission and 27% were in partial remission. Results included nine spontaneous abortions, one stillbirth, and five neonatal deaths. Thirty percent were premature births, and 33% were babies with low birth weight <2500 g. These outcomes were directly related to hypocomplementemia present at the time of conception and the use of aspirin during pregnancy [22].

Regarding kidney involvement, 33% had kidney flares (both during pregnancy and postpartum), 20 of these patients with reversible symptoms, and three with a progressive deterioration of glomerular filtration. One ended up on dialysis. These results were related to the maternal renal status prior to pregnancy.

In another study, they compared the results of pregnancy in patients with SLE who had already achieved clinical remission, taking into account the DORIS scale (definition of remission in SLE) and LLDAS (definition and initial validation of a lupus low disease activity state). A total of 49 patients were evaluated, when they were in modified clinical remission and 57 in modified LLDAS. In both groups, outcomes were similar: successful pregnancy, full-term births, fetal loss, miscarriage, smallfor-gestational-age infants, low-birth-weight infants, maternal complications, and flares [23].

Pharmacological therapy is another point that must be taken into account due to the potential teratogenic effect of some medications. In general, the therapy used in pregnant women with SLE is safe (prednisolone, azathioprine, and hydroxychloroquine [HCQ ]), and can even be continued without problems during lactation. However, in the case of women with lupus nephritis, many receive immunosuppressants such as mycophenolate mofetil (MMF), this drug has teratogenic potential (microtia and atresia of the external auditory canal, orofacial and cardiovascular malformations and digital hypoplasia), for which it should be discontinued before at least 6 weeks before conception in order not to have residual effects due to its enterohepatic circulation [24]. For these patients, the ideal would be to switch to azathioprine. In a study of 23 women with lupus nephritis with a low SLEDAI (Systemic Lupus Erythematosus Disease Activity Index) had switched to azathioprine before conception, there were no flares in 18 pregnancies and only one case in the postpartum period after 17 live births. It was also found that as the dose of prednisolone or SLEDAI was required to be increased, the prognosis of pregnancy worsened [25].

#### **4.1 Preeclampsia or lupus outbreak: "the great simulator":**

For several decades and until reactively recently, pregnancy in patients with SLE was discouraged due to the state of maximum activity with which it's related and deleterious consequences. It was routinely considered an absolute contraindication in these women. At present, according to the evidence, we know that it is possible to have a pregnancy with excellent outcomes as long as certain conditions are met (stable SLE or low activity in the 6 months prior to conception, since patients with active disease at this time have the highest risk of an outbreak during pregnancy), and that this is of strict multidisciplinary management. The PROMISSE study (Predictors of Pregnancy Outcome in SLE and antiphospholipid syndrome) determined the degree of risk of exacerbation in women with stable SLE and found that 385 women with SLE (31% with renal involvement/nephritis), the mild or moderate outbreaks reached 15%, while severe ones were 5%. Quite the opposite with patients who became pregnant with the active disease even 6 months earlier, where relapses reached almost 60% [26].

In a prospective study where the outcomes in the pregnancies of 132 women with SLE were studied, there were outbreaks of SLE in 75 of the 132 pregnancies, mild in 84 cases, moderate in 11, and severe in 19. Before pregnancy, 36% had glomerulonephritis, 33% had joint manifestations, 37% had comp hematological disease, 13% had a skin disease, 6% had neuropsychiatric manifestations, and 1% had serositis. During the 6 months before conception, 48% had mild and/or stable clinical manifestations. Anti-dsDNA antibodies were positive in 56% and anti-ENA antibodies in 47%: anti-Ro/SSA: 32.5%, anti-La/SSB: 1.5%, anti-U1RNP: 4.5% and anti-Sm: 6.8%. In the multivariate analysis, the indisputable predictor of relapse of any severity was the number of relapses that the patients had before pregnancy. In each of the groups of outbreaks, according to their severity, there were several predictors that warned about it: mild was associated with hematological abnormalities before pregnancy, moderate was due to low C3 or C4, and severe was due to having involved with renal compromise, some type of glomerulonephritis, before or

#### *Fertility, Pregnancy, and Systemic Lupus Erythematosus DOI: http://dx.doi.org/10.5772/intechopen.107036*

during conception. Protective factors it was observed the longer the duration of the disease there is more possibility. Joint involvement was predicted by anti-dsDNA positivity. Borella et al in made a study about pregnancy and SLE in which there were obtained 110 live births of 132 pregnancies. 81 were term babies and 29 were preterm. There were 22 losses: 14 miscarriages, seven stillbirths, and one volunteer. Fetal loss and small gestational age were associated with preeclampsia. Live births were obtained in 110 of the 132 pregnancies. Eighty-one were term babies and 29 were preterm. There were 22 losses: 14 miscarriages, seven stillbirths, and one volunteer. Fetal loss and small-for-gestational-age fetus were associated with hypertension at conception, miscarriage by a number of steroids taken in the last year before conception, stillbirth by a number of relapses in the last year before conception, premature birth and preeclampsia due to the coexistence of APS together with anti-dsDNA antibody levels before conception, and premature rupture of membranes due to a high ECLM (European Consensus Lupus Activity Measurement) score 6 months before conception. First births may be associated with a higher risk of exacerbation in SLE pregnancy compared to subsequent pregnancies, and the pattern of prior SLE involvement may be useful in predicting the course of SLE during pregnancy. Flare manifestations during a woman's pregnancy tend to reflect prior organ involvement [22].

In Asian cohort, 153 patients of 240 pregnancies predominantly Malaysia, India and China there were 61.7% of the cases with complications, being the most common prematurity, miscarriage and presence. Use of HCQ with decrease in complications including preeclampsia, prematurity and intrauterine growth restriction ( IUGR) [27].

In a cohort in Trinidad, a cross-sectional analysis and analysis of negative outcomes in pregnancies of 122 Afro-Caribbean women with SLE and without SLE was performed. In women with more that one pregnancy the total number of pregnancies as similar in women with or without diagnosis of SLE. A lower proportion of women with SLE had ever been pregnant compared to women without SLE. In multivariate logistic regression analysis, SLE pregnancies were more than twice as likely to end in stillbirth. The odds of early miscarriage and second-trimester miscarriage were higher in pregnancies with SLE than in pregnancies without SLE. Ectopic pregnancy and preterm birth were higher in pregnancies conceived after diagnosis. Evidence of high levels of both IgM and IgG lupus anticoagulant was found among women who reported three or more miscarriages and elevated IgG in cases of ectopic pregnancy [28].

Pregnancy outcomes in SLE patients, the effect of flare, and treatment on pregnancy outcomes were examined in a study conducted in Saudi Arabia. Pregnancies in patients with SLE and active lupus nephritis, with anti-Ro/SSA antibodies, aPL, hypertension, Raynaud's phenomenon, active disease at conception, and SLE exacerbations, were found to be at increased risk of adverse pregnancy outcomes [29] really without much difference with the other existing cohorts.

In Oman, a study found, apart from the complications already mentioned above where they do not differ from the rest, that pregnant patients with SLE and apart from antiphospholipid syndrome develop deep vein thrombosis and pulmonary embolism; therefore, it is a significant predictor of this type of complications (**Tables 1**–**3**) [30].

According to the Hopkins Center for the management of pregnancy in lupus patients, there have always been three major doubts over time, and thanks to the existing evidence we can know at this time. First, if there really is a greater probability that there will be outbreaks during pregnancy and if so, which organs and/ or systems will be most affected. Second, if there will be a renal compromise in these pregnancies and the third is if these patients really have a higher risk of presenting


Fetal loss (miscarriage or intrauterine fetal death)

Intrauterine growth restriction

Small-for-gestational-age newborns

Preeclampsia

HELLP syndrome (eclampsia/hemolysis, elevated liver enzymes, low platelets)

Premature rupture of membranes.

#### **Table 1.**

*Main complications in pregnancy in patients with SLE.*


#### **Table 2.**

*Factors directly proportional to SLE.*

Lupus nephritis = preeclampsia. (Both become indistinguishable)

Premature labor:


Patients with antiphospholipid antibody syndrome (APS) or SLE with positive antiphospholipid (aPL) with a history of pregnancy morbidity and thrombosis, presence of lupus anticoagulant, and triple positivity for aPL antibodies.

#### **Table 3.**

*Most common and/or expected adverse results.*

complications at the obstetric level. Today, we know that the answer is yes to everything. There is definitely a risk that outbreaks are more common during pregnancy, obtaining similar results in the different cohorts existing at the time, which include patients of all kinds of races, ethnicities, socioeconomic strata, associated comorbidities, etc. These factors are determining [31]. For example, in American studies, more than half of the patients are African–American. In this group of patients, the flare rate is much higher than in Caucasian patients and similar to Indian patients. Outbreaks in the renal and hematologic systems increase during pregnancy, whereas the involvement of the musculoskeletal system is less.

The differentiate lupus flare from preeclampsia, we have certain clinical predictors such as decreased complement serum levels, normal blood pressure and good response to prednisone, the latter use of intravenous to compare will worsen preeclampsia, howewer, it is necessary compare and analize the risk vs. benefity. Now there is the possibility of advising patients with lupus that despite having a lupus flare, their pregnancy can continue and at the same time decrease the activity of the disease as long as the rheumatologist, obstetrician, perinatologist, and other

*Fertility, Pregnancy, and Systemic Lupus Erythematosus DOI: http://dx.doi.org/10.5772/intechopen.107036*

multidisciplinary team are pending the development and outcome of pregnancy. Because the arsenal of medications allowed in pregnancy is limited, in the acute management of a lupus flare that endangers the lives of patients, sometimes it is necessary to choose between fetal and maternal well-being. The beauty of this is that lupus activity can be controled with prednisone, HCQ and azathioprine. For moderate flare-ups, prednisone at 1 m/k is used, for urgent situations such as severe flare ups, pulses of intravenous methylprednisolone 1000 mg/day dose, for 3 days it's effective.

One of the culprits in pregnant women is for lupus outbreaks apart from estrogens, is prolactin. This is associated with increased disease activity [32]. These patients also have a higher rate of complications in terms of morbidity, especially in relation to metabolic disorders (gestational diabetes and hyperglycemia), hypertensive disorders of pregnancy (including preeclampsia), and urinary tract infections. Greater complications during labor have also been shown, they have a higher risk of premature rupture of membranes and require cesarean sections in a greater proportion than healthy women [33]. In addition, women with SLE who develop anti-prolactin antibodies during their pregnancy are less likely to have both maternal and fetal complications compared to those who do not. For this reason, the administration of bromocriptine with the purpose of blocking prolactin is accepted as a way of preventing relapses during pregnancy and, in turn, obtaining a good result for both the mother and the product. It is administered even postpartum as it is related to less use of immunosuppressants and steroids [34].
